Appropriate ovarian development and function require mechanisms regulating growth and steroidogenesis of theca-interstitial cells. Under pathological conditions such as polycystic ovary syndrome (PCOS), theca-interstitial compartment is hyperplastic and produces excessive amounts of androgens. This proposal is designed to test the novel hypothesis that the mevalonate pathway plays an important role in modulation of growth and function of the ovarian theca-interstitial cells. We postulate that mevalonate pathway affects theca-interstitial cells by: (i) altering isoprenylation of small GTPases such as Ras and Rho affecting thus signal transduction pathways regulating growth, (ii) modulating the availability of substrates for steroidogenesis, and (iii) altering the level of oxidative stress, which, in turn, affects growth and steroidogenesis. Ultimately, we propose that, inhibition of the mevalonate pathway by agents such as statins may correct major features of PCOS including excessive growth of theca-interstitial cells, excessive androgen production and oxidative stress. This hypothesis is based on evidence that in several tissues, such as vascular smooth muscle, products of the mevalonate pathway facilitate isoprenylation of small GTPases and thus activate signal transduction pathways promoting growth. In vascular smooth muscle and in several other tissues, inhibition of the mevalonate pathway by statins inhibits growth, exerts antioxidant effects and decreases cholesterol synthesis. Our preliminary studies have shown that moderate oxidative stress increases and statins inhibit proliferation and steroidogenesis of theca-interstitial cells while blocking ERK1/2 phosphorylation. We have also completed a pilot clinical trial and we found that simvastatin decreases testosterone and luteinizing hormone in women with PCOS. The specific aims of this proposal are to study in depth the role of the mevalonate pathway in theca-interstitial cells on: (i) growth, (ii) steroidogenesis and (iii) oxidative stress. These aims will be addressed by experiments on rat and human theca-interstitial cell cultures. The results of these studies will provide a new insight into the role of mevalonate pathway on the growth and function of ovarian mesenchyme. Ultimately, the proposed research may shed new light on the pathophysiology of PCOS and provide an impetus towards the development of new therapeutic approaches, such as clinical use of statins. [unreadable] [unreadable] [unreadable]